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Aberrant Complement Activation Is Associated With Structural Brain Damage in Multiple Sclerosis
Johanna Oechtering1,2, Sabine Anna Schaedelin2,3, Kerstin Stein4
1Department of Neurology, University Hospital and University of Basel.
Neurology(R) Neuroimmunology & Neuroinflammation
|January 3, 2025
Summary
Complement activation in cerebrospinal fluid is linked to multiple sclerosis (MS) progression and brain damage. Targeting the complement system may help reduce MS-related disability.
Area of Science:
- Neuroimmunology
- Complement System Biology
- Neurology
Background:
- Elevated complement protein levels in cerebrospinal fluid (CSF) correlate with multiple sclerosis (MS) severity.
- Understanding the relationship between complement activation and MS disease activity is crucial for therapeutic development.
Purpose of the Study:
- To investigate if complement activation profiles in CSF correlate with quantitative MRI metrics and liquid biomarkers of MS disease activity and progression.
- To determine the association between specific complement components and markers of neurodegeneration and inflammation in MS.
Main Methods:
- Quantified 12 complement components and activation products in the CSF of 112 patients with clinically isolated syndromes and 127 with MS.
- Assessed longitudinal MRIs and quantified liquid biomarkers including neurofilament light chain, GFAP, CXCL-13, CXCL-9, and IL-12b.
- Utilized multivariable models to analyze associations between complement parameters and MRI/biomarker outcomes.
Main Results:
- Complement components C4a, Ba, and C3a were strongly associated with accelerated brain atrophy and increased T2-weighted lesion volumes.
- C3a and Ba correlated with higher odds of contrast-enhancing lesions (CELs) and increased incidence rates of paramagnetic rim lesions (PRLs).
- C1q, C3a, and C4a were linked to elevated glial fibrillary acidic protein (GFAP) levels, indicating neuroinflammation.
Conclusions:
- Intrathecal complement activation is consistently associated with MRI metrics and biomarkers of MS disease activity and progression.
- Aberrant complement activation significantly correlates with structural brain damage in MS.
- Targeting the complement system presents a potential therapeutic strategy to mitigate disability accumulation in MS.
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